Since the Garden of Eden and the trees of knowledge and life, the connection between food, cognition and survival has been recognized. Today, nutritional status is a well-accepted regulator of neural function and longevity.
Studies have shown that mild energy restriction (to 60% of control) improves cognitive function while severe restriction (to 40%) prejudices it. Such cognitive dysfunction may manifest as deficits in hippocampal-dependent learning and memory, including spatial information processing. The benefits of mild energy restriction have been repeatedly demonstrated in prolonging longevity and in improving neurodegenerative diseases. Understanding of the mechanisms for neural damage advanced when apoptosis was shown to be responsible for some of the neural cell loss found in Parkinson's and in Alzheimer's disease. Neuroapoptotic cell death is a multi-step process involving several key molecules, modulation of which may inhibit the process. Such neuroprotective agents were also found to overcome poor behavioral performance found in animal models for these diseases1,2.
The mammalian forebrain contains populations of cells that divide and differentiate into neurons and glia. These neurons are generated continuously from stem cells in specific regions of the adult brain. Such constitutive neurogenesis can be modulated by changes in diet. Reduced nutritional status in mice increased the numbers of newly generated cells primarily in the dentate gyrus of the hippocampus3,4, which is the principal center for learning and memory5; suppression of neurogenesis led to impaired learning and memory6.
Cellular energy status is monitored and controlled by the 5′-AMP-activated protein kinase (AMPK) system. AMPK and its homologue in Saccharomyces cerevisiae are allosterically activated by 5′-AMP, which accumulates following ATP hydrolysis. 5′-AMP may also promote phosphorylation and activation of AMPK by an upstream kinase. Conversely, high ATP antagonizes the activating effects of 5′-AMP on AMPK. Stresses such as hypoxia, heat shock, metabolic poisoning and exercise, all activate AMPK by their effect on the ratio of 5-AMP to ATP. AMPK, in turn, phosphorylates multiple targets, which switch off anabolic pathways and stimulate catabolic ones7. Recent studies have demonstrated that this activation regulates intracellular signaling pathways involved in cellular survival and apoptotic cell death in endothelial cells, liver, pancreatic beta cells and other tissues8,9,10. AMPK is considered to act as a “fuel gauge” for cellular metabolism, controlling the endogenous energy supply of ATP. It was not surprising therefore, when AMPK was also found to regulate feeding behavior11, 12.
Leptin is an adipokine hormone that plays a central role in food intake, energy balance and body weight regulation, mainly through its hypothalamic receptors13, 14, 15. Studies on leptin function have demonstrated that AMPK is essential for mediating its actions16. While leptin exerts its catabolic effects in the periphery by stimulating AMPK phosphorylation and activation, its central effects on energy balance act through hypothalamic AMPK dephosphorylation and inhibition11,12.
There are also leptin receptors in the hippocampus but its role in memory learning and cognitive functions has never been elucidated.